Deficiencies in the innate immune response of HIV infected people and FIV infected cats are well documented. The defect often presents clinically as reduced competence in eliminating intracellular opportunistic pathogens. Not only is innate immunity responsible for the control and elimination of the majority of opportunistic infections, it is the innate response that initiates the type and strength of the adaptive immune response. We have employed Listeria monocytogenes (LM) as an immune system probe to investigate the effects of FIV infection on innate immune function. We have found that the innate immune response to LM is impaired in acutely and chronically FIV infected cats. We also determined that locally administered IL15 could improve the innate immune response and that this was associated with increased NK cells in draining lymph nodes. Activated, mature dendritic cells (DC) play a key role in initiating the innate immune response by recruiting and activating NK cells and modulating Treg function. It is now clear that cross-talk between DC, NK cells and Treg is critical for coordination of the innate response. As such, these three cell types create a fundamental regulatory axis for innate responses and subsequent adaptive responses. We will determine the contribution of each of these cell types to the innate immune defect associated with FIV infection. Specific Aim 1 will determine whether incomplete DC maturation could underlie innate immune dysfunction during lentivirus infection and whether dendritic cells in FIV infected animals respond normally to TLR ligands. Specific Aim 2 will determine the nature and mechanism of NK cell dysfunction in vivo. Specifically, this aim will assess NK cell chemotaxis, proliferation and function during an innate immune challenge of FIV+ cats, whether DC-NK cross-talk results in NK cell activation, and whether systemic IL15 treatment restores innate immune function. Specific Aim 3 will determine if regulatory T cells suppress innate immune function in FIV infected cats, whether such an effect is mediated by TGF-[unreadable] and if Treg are preferentially induced by DC. Together these studies will elucidate the cellular mechanisms that underlie the innate immune defect and investigate potential molecular mechanisms.